Interstitial pneumonia is a disease that is characterized by cardinal symptoms such as dry cough and shortness of breath and is sometimes accompanied by fever and arthralgia, while other systemic symptoms develop in case interstitial pneumonia is complicated with the systemic disease.
Interstitial pneumonia can be clinically classified into an acute form and a chronic form. Hamman-Rich syndrome is thought to be the acute form. Although steroid is generally used in the treatment of interstitial pneumonia, poor prognosis for interstitial pneumonia often causes pulmonary fibrosis, which leads to severe course. Therefore, there is required a novel remedy for treatment of interstitial pneumonia, as well as prevention and treatment of pulmonary fibrosis.
A proper animal model of interstitial pneumonia has never been known, although it has hitherto been known administering bleomycin or silica to a mouse induces pulmonary fibrosis.
Interleukin 18 (IL-18) is the latest cytokine which was discovered as interferon γ (IFN-γ) inducible factor [IGIF] by macrophages in 1995 [Nature 378, 88-91(1995)]. IL-18 is synthesized as a precursor (pro IL-18) and then converted into an activated type (mature IL-18) by cleavage using an interleukin 1 β-converting enzyme [caspase-1] and so on. A precursor of mouse IL-18 comprises 192 amino acids and an activated one thereof comprises 157 amino acids.
Also a precursor of human IL-18 comprises 193 amino acids and an activated one thereof comprises 157 amino acids.
A receptor of IL-18 belongs to an IL-1 receptor family, and receptor components (IL-18Rα and IL-18Rβ) are known.
It is known that IL-18 acts on helper T cell 1 (Th1) and natural killer cells (NK cells) to induce the production of IFN-γ and also enhances a cytotoxic T cell activity to enhance a cytotoxicity. Therefore, IL-18 is considered to be an inflammatory cytokine which induces Th1 response.
Thus, a relation between type 1 diabetes mellitus [DM], multiple sclerosis and Crohn's disease caused by the Th1 overresponse and IL-18 has attracted special interest.
However, any relation between interstitial pneumonia and IL-18 had never been known.
Interleukin 2 (IL-2) is a cytokine secreted mainly by T cells (CD4+, CD8+) and comprises 133 amino acids. IL-2 is also referred to as a T cell growth factor (TCGF) and causes the growth of T cells. It is known that IL-2 exerts an action on not only T cells, but also B cells, NK cells, macrophages and neutrophilic leukocytes and so on. On the surface of these cells, an IL-2 receptor is expressed. The IL-2 receptor is a complex comprising α chain, β chain and γ chain subunits. The α chain is also referred to as a Tac antigen and comprises 251 amino acids. The γ chain is a second subunit of an IL-4 receptor, IL-7 receptor and an IL-9 receptor, while β chain and γ chain subunits are second and third subunits of an IL-15 receptor.
International Application WO99/51580 discloses that a pyrazole derivative capable of inhibiting the production of IL-2 is used in the treatment of immune-related disease, and also describes pulmonary fibrosis and idiopathic interstitial pneumonia among various diseases listed as the immune-related disease.
However, there is not any concrete description about a therapeutic effect based on the inhibition of the production of IL-2 in any diseases listed in the publication.